1. Field of the Invention
The present invention generally relates to formulations of quaternary ammonium neuromuscular blocking agents such as vecuronium, rocuronium, pancuronium, etc. which are used as skeletal muscle relaxants, for endotracheal tube insertion, and for other applications, where the formulations are designed to be water-continuous, low viscosity, safe for injection, and ready to use, but where contact between water and the hydrolyzable groups on the drug are limited so as to reduce the rate of hydrolysis and improve stability and shelf life.
2. Background Description
Salts of quaternary ammonium compounds such as vecuronium, rocuronium and pancuronium are currently used as skeletal muscle relaxants, and are generally given by intravenous injection prior to intubation, for example. Their rapid onset and short-acting behavior are key features to the success of these drugs. In the case of vecuronium bromide, a dose of 0.08 to 0.1 mg/Kg generally produces first depression of twitch response, under balanced anesthesia, in approximately 1 minute, with good or excellent intubation conditions within 2.5 to 3 minutes, with recovery 95% complete within 45 to 65 minutes.
However, many of the active pharmaceutical compounds in this class, and especially the marketed vecuronium and pancuronium formulations, are hydrolytically unstable, with rocuronium being rather more stable. In particular the acetate ester groups hydrolyze over time in aqueous solution, thereby potentially reducing efficacy, impacting safety, and limiting shelf life. Three methods have been used to limit this hydrolysis, each of which has distinct drawbacks and/or limitations. One method is to lower the hydrolysis rate by storing the product at refrigerator temperatures, as opposed to ambient. This method significantly increases the cost, and reduces convenience, for any of these compounds, and at least in the most unstable compounds in the class, such as vecuronium bromide, only extends room temperature shelf life by less than about 6 months. Another method is to formulate the product as an aqueous solution at low pH which reduces the hydrolysis rate. For example, a formulation of pancuronium bromide has been marketed by Gensia-Sicor Pharmaceuticals which has a pH of 3.8-4.2. Two problems result from this acidic pH: stinging upon injection, and a tendency to induce dangerous precipitation of other drug formulations administered in conjunction with the muscle relaxant, in particular sedatives such as thiopental sodium. In addition, the above two methods still do not solve the hydrolysis problem but only lengthen the shelf-life moderately. A third method is to formulate the drug as a reconstitutable powder, to which water for injection is added just prior to use. This introduces another step in the surgeon's or anesthesiologist's regiment, so is undesirable for that reason alone. In addition, such reconstitutable formulations must typically be sterilized by expensive gamma irradiation sterile fill procedures. Furthermore, in the event that not all the drug is re-dissolved or re-dispersed during the pre-injection step, this could lead to dangerous emboli, such as pulmonary emboli.
Quaternary ammonium skeletal muscle relaxants have in common a unique combination of structural and physicochemical characteristics that make their incorporation into a stable formulation challenging. To begin with, they have at least one (and in the case of pancuronium, for example, two) permanent cationic charge(s) (quaternary ammonium), giving the molecule a positive charge at essentially all values of pH, and certainly at all values of pH relevant to drug delivery. Since nearly all pharmaceutically acceptable ionic surfactants are anionic, the presence of a drug with a cationic charge will act to reduce the magnitude of the zeta potential for virtually any type of particle or droplet. This can render conventional attempts to achieve electrostatic stabilization ineffective, or cause required levels of surfactant to increase significantly, thus exacerbating their undesirable effects. A second characteristic shared by these compounds is a significant hydrophobic moiety within the molecule, typically a 19-carbon steroidal ring system (counting the side methyl groups), which nonetheless does not yield a high octanol-water partition coefficient for the drug. This is a major hurdle for many common formulation schemes for protecting active compounds from water contact. Since octanol-water partition coefficients of the entire class of quaternary ammonium skeletal muscle relaxants will generally be quite low, less than 1.0 (i.e., low Kow<0), this tends to teach away from the use of lipid-based vehicles in attempting to reduce water-drug contact for these compounds. In addition, the solubility of these drugs in glycerol and other injectable solvents is generally very low. Hence, drugs in the quaternary ammonium neuromuscular blocking agent class possess a combination of characteristics that intertwine and make the formulation of such a compound in a protective milieu very challenging.